Acetyl-CoA metabolism as a therapeutic target for cancer

Chen, Guo; Bao, Banghe; Cheng, Yang; Tian, Minxiu; Song, Jiyu; Zheng, Liduan; Tong, Qiangsong

doi:10.1016/j.biopha.2023.115741

Cited by 8 publications

(2 citation statements)

References 307 publications

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“…In non-cancerous liver cells, Acetyl-CoA is a central metabolic intermediate, and the maintenance of the Acetyl CoA pool is essential for growth, proliferation, and protein modification. Cancer cells have developed the capacity to capture acetate as an alternative source to glucose from the circulation and even from the intestinal microbiome [ 49 , 50 ]. In the present work, we show that in human HCC, many of the metabolic pathways using Acetyl-CoA—such as lipid biosynthesis—are downregulated when compared with not-tumoral tissues.…”

Section: Discussionmentioning

confidence: 99%

Application of Graph Models to the Identification of Transcriptomic Oncometabolic Pathways in Human Hepatocellular Carcinoma

Barace,

Santamaría,

Infante

et al. 2024

Biomolecules

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Whole-tissue transcriptomic analyses have been helpful to characterize molecular subtypes of hepatocellular carcinoma (HCC). Metabolic subtypes of human HCC have been defined, yet whether these different metabolic classes are clinically relevant or derive in actionable cancer vulnerabilities is still an unanswered question. Publicly available gene sets or gene signatures have been used to infer functional changes through gene set enrichment methods. However, metabolism-related gene signatures are poorly co-expressed when applied to a biological context. Here, we apply a simple method to infer highly consistent signatures using graph-based statistics. Using the Cancer Genome Atlas Liver Hepatocellular cohort (LIHC), we describe the main metabolic clusters and their relationship with commonly used molecular classes, and with the presence of TP53 or CTNNB1 driver mutations. We find similar results in our validation cohort, the LIRI-JP cohort. We describe how previously described metabolic subtypes could not have therapeutic relevance due to their overall downregulation when compared to non-tumoral liver, and identify N-glycan, mevalonate and sphingolipid biosynthetic pathways as the hallmark of the oncogenic shift of the use of acetyl-coenzyme A in HCC metabolism. Finally, using DepMap data, we demonstrate metabolic vulnerabilities in HCC cell lines.

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Section: Discussionmentioning

confidence: 99%

Application of Graph Models to the Identification of Transcriptomic Oncometabolic Pathways in Human Hepatocellular Carcinoma

Barace,

Santamaría,

Infante

et al. 2024

Biomolecules

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“…ACSS2 thus plays key roles for epigenetic regulation and metabolic homeostasis in different pathophysiological settings (e.g. [1,2]) and has emerged as a new drug target for cancer [3].…”

Section: Introductionmentioning

confidence: 99%

Cytosolic acetyl-CoA synthetase (ACSS2) does not generate butyryl- and crotonyl-CoA

Zeaiter,

Belot,

Cunin

et al. 2023

Preprint

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Acetyl and other acyl groups from different short-chain fatty acids (SCFA) competitively modify histones at various lysine sites. To fully understand the functional significance of such histone acylation, a key epigenetic mechanism, it is crucial to characterize the cellular sources of the corresponding acyl-CoA molecules required for the lysine modification. Like acetate, SCFAs such as propionate, butyrate and crotonate are thought to be the substrates used to generate the corresponding acyl-CoAs by enzymes known as acyl-CoA synthetases. The acetyl-CoA synthetase, ACSS2, which produces acetyl-CoA from acetate in the nucleocytoplasmic compartment, has been proposed to also mediate the synthesis of acyl-CoAs such as butyryl- and crotonyl-CoA from the corresponding SCFAs. This idea is now widely accepted and is sparking new research projects. However, based on our directin vitroexperiments with purified or recombinant enzymes and structural considerations, we demonstrate that ACSS2 is unable to mediate the generation of non-acetyl acyl-CoAs like butyryl- and crotonyl-CoA. It is therefore essential to re-examine published data and corresponding discussions in the light of this new finding.

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HDAC8 Enhances the Function of HIF‐2α by Deacetylating ETS1 to Decrease the Sensitivity of TKIs in ccRCC

Qian,

Li,

Ren

et al. 2024

Advanced Science

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Drug resistance after long‐term use of Tyrosine kinase inhibitors (TKIs) has become an obstacle for prolonging the survival time of patients with clear cell renal cell carcinoma (ccRCC). Here, genome‐wide CRISPR‐based screening to reveal that HDAC8 is involved in decreasing the sensitivity of ccRCC cells to sunitinib is applied. Mechanically, HDAC8 deacetylated ETS1 at the K245 site to promote the interaction between ETS1 and HIF‐2α and enhance the transcriptional activity of the ETS1/HIF‐2α complex. However, the antitumor effect of inhibiting HDAC8 on sensitized TKI is not very satisfactory. Subsequently, inhibition of HDAC8 increased the expression of NEK1, and up‐regulated NEK1 phosphorylated ETS1 at the T241 site to promote the interaction between ETS1 and HIF‐2α by impeded acetylation at ETS1‐K245 site is showed. Moreover, TKI treatment increased the expression of HDAC8 by inhibiting STAT3 phosphorylation in ccRCC cells is also found. These 2 findings highlight a potential mechanism of acquired resistance to TKIs and HDAC8 inhibitors in ccRCC. Finally, HDAC8‐in‐PROTACs to optimize the effects of HDAC8 inhibitors through degrading HDAC8 and overcoming the resistance of ccRCC to TKIs are synthesized. Collectively, the results revealed HDAC8 as a potential therapeutic candidate for resistance to ccRCC‐targeted therapies.

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Acetyl-CoA metabolism as a therapeutic target for cancer

Cited by 8 publications

References 307 publications

Application of Graph Models to the Identification of Transcriptomic Oncometabolic Pathways in Human Hepatocellular Carcinoma

Application of Graph Models to the Identification of Transcriptomic Oncometabolic Pathways in Human Hepatocellular Carcinoma

Cytosolic acetyl-CoA synthetase (ACSS2) does not generate butyryl- and crotonyl-CoA

HDAC8 Enhances the Function of HIF‐2α by Deacetylating ETS1 to Decrease the Sensitivity of TKIs in ccRCC

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